Interferons, including interferon-.alpha. ("IFN.alpha.") and interferon-.beta. ("IFN.beta."), were among the first of the cytokines to be produced by recombinant DNA technology. IFN.alpha. has been shown to have therapeutic value in conditions such as inflammatory, viral, and malignant diseases. IFN.beta. has been approved for use in treatment of multiple sclerosis.
Most cytokines, including IFN.beta., have relatively short circulation half-lives since they are produced in vivo to act locally and transiently. To use IFN.beta. as an effective systemic therapeutic, one needs relatively large doses and frequent administrations. Such frequent parenteral administrations are inconvenient and painful. Further, toxic side effects are associated with IFN.beta. administration which are so severe that some multiple sclerosis patients cannot tolerate the treatment. These side effects are probably assciated with administration of a high dosage.
To overcome these disadvantages, one can modify the molecule to increase its circulation half-life or change the drug=s formulation to extend its release time. The dosage and administration frequency can then be reduced while increasing the efficacy. With respect to interferon-.alpha., which suffers from the same disadvantages, efforts have been made to create a recombinant IFN.alpha.-gelatin conjugate with an extended retention time (Tabata, Y. et al., Cancer Res. 51:5532-8, 1991). A lipid-based encapsulated IFN.alpha. formulation has also been tested in animals and achieved an extended release of the protein in the peritoneum (Bonetti, A. and Kim, S. Cancer Chemother Pharmacol. 33:258-261, 1993).
Immunoglobulins of IgG and IgM class are among the most abundant proteins in the human blood. They circulate with half-lives ranging from several days to 21 days. IgG has been found to increase the half-lives of several ligand binding proteins (receptors) when used to form recombinant hybrids, including the soluble CD4 molecule, LHR, and the IFN-.gamma. receptor (Mordenti J. et al., Nature, 337:525-31, 1989, Capon, D. J. and Lasky, L. A., U.S. Pat. No. 5,116,964; Kurschner, C. et al., J. Immunol. 149:4096-4100, 1992). However, such hybrids can present problems in that the peptide at the C-terminal of the active moeity and the peptide at the N-terminal of the Fc portion at the fusion point creates a new peptide sequence, which is a neoantigen, and which can be immunogenic. The invention relates to a IFN.beta.-Fc hybrid which is designed to overcome this problem and extend the half-life of the IFN.beta..